In vivo administration of parathyroid hormone (PTH) stimulates new bone formation in experimental animals and humans. Although IGF-1 mediates some of the effects of PTH in bone, the role of other growth factors has not been elucidated. PTH is an essential regulator of calcium metabolism and also has catabolic effects on bone. Similar to PTH, basic fibroblast growth factor (FGF-2) is a potent bone anabolic agent when administered to rodents in vivo and also stimulates osteoclast formation and bone resorption. We have shown that PTH increased FGF-2 and FGF receptor (FGFR) expression in cell cultures of osteoblastic cells as well as in bone organ cultures. We have shown that short term FGF-2 treatment of mouse bone marrow stromal cells increased PTH Receptor 1, IGF-1 and Runx-2 expression and mineralized bone nodule formation. Furthermore, our preliminary studies show that the ability of PTH to stimulate osteoclast formation in murine bone marrow cultures, to increase serum calcium and to increase bone formation in vivo are all significantly reduced in mice with disruption of the Fgf2 gene suggesting an important physiologic role for endogenous FGF-2 in some of the responses to PTH in bone. It is not clear whether the reduced anabolic response to PTH in the Fgf2-/- mice is due to effects on bone remodeling at the level of the osteoblast or the osteoclast. Preliminary studies show that the cAMP response to PTH is similar in marrow stromal cells (from both genotypes) grown under differentiation conditions. PTH stimulates osteoclast formation via activation of RANKL. Interestingly, the ability of RANKL to stimulate osteoclast formation and to activate p38MAP kinase that is important in osteoclast formation is also impaired in marrow cultures from the Fgf2 -/- mice. The focus of this grant is to determine the role of endogenous FGF-2 in PTH induced bone remodeling in mice. The overall hypothesis is that endogenous FGF-2 is a necessary co-factor for maximal anabolic and resportive effects of PTH in bone. Modulation of endogenous FGF-2 by PTH could have therapeutic implications. Specific Aim 1: To determine whether FGF-2 deficiency modulates the anabolic response to PTH. Specific Aim 2a. To assess whether FGF-2 deficiency affects PTH induced osteoblast proliferation, differentiation, apoptosis and bone nodule formation. Specific Aim 2b: To examine the effect Fgf2 deficiency on osteoclastogenesis in response to PTH in Fgf2-/- mice. Specific Aim 3: To determine whether Fgf2 deficiency alters key signaling molecules that mediate PTH induced responses in bone. The results of the proposed studies could increase our understanding of the molecular mechanism(s) of the effect of PTH on bone. If FGF2 is critical for the PTH anabolic effect, then analysis of this interaction could lead to a new approach to anabolic therapy